Lung surfactant proteins SP-B and SP-C are required for the biophysical activity of lung surfactant (LS), the complex lipid-protein mixture that coats the internal air-liquid (a/l) interface of the vertebrate lung and reduces the work of breathing.1,2 Both proteins (˜1.5-2.0 combined wt % of natural LS) contain a high proportion of lipophilic residues, and they adopt amphiphilic and helical conformations. The main function of LS is to regulate surface tension (γ, mN m−1) in the alveoli (tiny sacs that mediate gas exchange between the blood and air spaces of the lung) by optimizing available surface area, maximizing lung compliance, and stabilizing the alveolar network against collapse.3 Three crucial functional characteristics of LS are: (1) rapid adsorption to the a/l interface, (2) near-zero γ upon film compression, and (3) efficient re-spreading of material and minimal loss to the subphase through multiple breathing cycles.4 
Deficient or dysfunctional LS results in infant or acute respiratory distress syndromes (IRDS or ARDS, respectively).5,6 Although no current exogenous treatment for ARDS exists,7 IRDS can be successfully treated with porcine- or bovine-derived surfactant replacement therapies (SRTs).8 Use of animal-derived substances, however, is non-ideal because of the risk of zoonotic infection and the high cost of large-scale extraction, isolation, and purification. To eliminate dependence on animal-derived material, many groups have sought to develop biomimetic LS replacements based on synthetic surfactant protein analogues.4 This approach could lead to a safe and bioavailable alternative to SRTs that may be able to treat or mitigate both IRDS and ARDS.
SP-B in monomeric form is a 79-residue protein (8.7 kDa) with a net cationic charge, and is postulated to contain four or five facially amphiphilic helices. SP-B forms four disulfide bonds: three intramolecular connections that presumably constrain conformational flexibility, and one intermolecular bond that results in homodimerization.9-12 SP-C contains just 35 residues and forms a single helix.13 This protein has two palmitoylation points (positions 5 and 6), two cationic residues (11 and 12), and an extremely lipophilic poly-valine helix that approximates the length necessary for spanning a lipid bilayer.12,14-17 The sequences and structural attributes of both proteins are highly conserved across mammalian species, implying that these features are necessary for their ability to organize and regulate lipid film formation, and to anchor the film to the a/l interface.3,18 Unfortunately, these attributes render the proteins very troublesome to obtain on a large scale by extraction or chemical synthesis; efforts to synthesize SP-B or SP-C or fragments thereof are often hampered by misfolding or aggregation.4 
The main approaches toward functional mimicry of surfactant proteins have involved peptide fragment synthesis, limited dimerization of SP-B, recombinant protein expression, and more recently, peptoid synthesis, the subject of recent contributions in this field.19-24 Although a recombinant form of SP-C is available,25 it is not palmitoylated, and no recombinant form of SP-B has yet been reported. Chemically synthesized, surface-active peptide fragments of SP-B such as SP-B1-2526,27 and the dimeric constructs dSP-B1-2528 and “Mini-B”,29 have demonstrated in vitro and in vivo success, but the challenge of generating these materials on a large scale is a stumbling block to pharmaceutical development. The chronic problem of achieving the desired extent of dimerization and multiple amphiphilic helices when mimicking SP-B has prompted recent endeavors to determine whether the incorporation of dimerization points can be circumvented while retaining good surfactant activity.24,30 
The high cost of large-scale, step-wise synthesis and purification represents a significant barrier to the development of peptide-based drugs and has generated an interest in alternatives for use in an LS replacement.4 Non-natural oligomers, such as peptoids,31 β-peptides32,33 and α/β-peptides34,35 can circumvent some peptide-associated problems, including irreversible aggregation and protease susceptibility; however, step-wise synthesis is required for preparation of these sequence-specific oligomers, and reversed-phase high performance liquid chromatography (RP-HPLC) is necessary for their purification.32,36 Therefore, although these types of peptide mimics can display impressive biological activities and thereby shed light on relationships between molecular structure and resultant biophysical activities, sequence-specific non-natural oligomers do not alleviate the production cost problem.